Prevention of renarcotization from synthetic opioids

项目摘要/摘要 2017年10月，美国政府宣布目前的阿片类药物流行是美国最严重的毒品危机 历史。合成衍生阿片类药物，如芬太尼和芬太尼衍生物，一直处于 这一突发公共卫生事件，显示出每年对过量死亡的最高贡献。而当 MU阿片受体(MOR)拮抗剂纳洛酮已被证明是一种宝贵的阿片类药物过量解毒剂， 纳洛酮的作用时间很短(半衰期约为1小时)。并已被发现效率较低 对抗较新的长效阿片类药物，包括芬太尼(半衰期~7-10小时)。这导致了一种高度致命的 越来越普遍的现象被称为“再矿化”，在这种现象中，过量服药的患者苏醒过来 纳洛酮可以通过体内残留的芬太尼重新进入过量状态。 为了对抗再矿化，纳洛酮必须反复给药，而且剂量明显高于芬太尼。 这种方法可以在医院内实现；但是，在医院以外的地方通常不能识别重新区域化 医疗环境，并可能导致死亡。因此，迫切需要开发一种长效的MOR拮抗剂。 可通过提供多小时保护来解决重碳化问题的配方。 这个第一阶段STTR项目的目标是使用FDA批准的微胶囊重新配制纳洛酮 技术制成长效注射剂(LAI)，可提供12-24小时。体内持续的拮抗剂活性。 通过化学修饰纳洛酮来解决这一问题的其他尝试可能会受到重大监管 和技术风险。Consegna的创新是使用其专有的计算药物输送™软件， 称为adsr™，用于进行硅胶处方优化以及预测其体外溶出度和 体内药代动力学行为。可通过505(B)(2)加速监管途径寻求批准，以 近期进入市场，因为纳洛酮分子没有被修饰，疗效不存在风险。 这种名为CP216的新长效纳洛酮配方将利用创新设计来解决这两个问题 通过联合应用游离形式的纳洛酮治疗原发和继发性过量用药(再矿化) 即刻生效和微囊化纳洛酮持续保护。 我们的假设是纳洛酮从微粒中的持续释放，加上立即释放的 游离纳洛酮可以提供逆转过量用药和防止再矿化所需的治疗水平。 为了验证这一假设，1)设计适当的微粒配方并评估配方的 有效载荷和体外释放行为，2)在动物模型中评估药物动力学，以及3)完成 化学、制造和控制组件的设计质量评估。康塞格纳相信这一点 该项目具有巨大的潜力，可以带来第一个安全有效的产品来解决重新合法化问题，以及 将对公众健康产生积极影响。

PROJECT SUMMARY/ABSTRACT In October 2017, the U.S. Government declared the current opioid epidemic the worst drug crisis in American history. Synthetically derived opioids such as fentanyl and fentanyl-derivatives have been at the forefront of this public health emergency, exhibiting the highest year-to-year contribution to overdose deaths. While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life ~ 1hr.) and has been found to be less effective against newer, long acting opioids including fentanyl (half-life ~7-10 hrs.). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization”, wherein an overdose patient revived with naloxone can re-enter an overdose state from residual fentanyl in the body. To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses than fentanyl. This approach may be achievable in a hospital; however, renarcotization is often not recognized outside a medical setting and can lead to death. Thus, there is a critical need to develop a long acting MOR antagonist formulation that can address renarcotization by providing the multi-hour protection. The goal of this Phase I STTR project is to reformulate naloxone using FDA approved microencapsulation technology into a long acting injectable (LAI) that can provide 12-24 hrs. of sustained antagonist activity in vivo. Other attempts to address this issue by chemically modifying naloxone are likely to suffer significant regulatory and technical risk. Consegna’s innovation is to employ its proprietary Computational Drug Delivery™ software, called ADSR™, to perform in silico formulation optimization as well as to predict its in vitro dissolution and in vivo pharmacokinetic behavior. Approval can be sought thru the 505(b)(2) accelerated regulatory pathway to gain near-term entry into the market since the naloxone molecule is not modified and efficacy is not at risk. This new long acting naloxone formulation, named CP216, will utilize an innovative design to address both primary and secondary overdose (renarcotization) situations thru a combination of free form naloxone for immediate effect and microencapsulated naloxone for sustained protection. Our hypothesis is that sustained release of naloxone from microparticles, coupled with an immediate release of free naloxone, can provide the therapeutics levels needed to reverse the overdose and prevent renarcotization. To test this hypothesis, 1) design an appropriate microparticle formulation and assess the formulation’s payload and release behavior in vitro, 2) evaluate the pharmacokinetics in an animal model, and 3) complete a Quality-by-Design assessment for a Chemistry, Manufacturing, and Controls package. Consegna believes this project has a significant potential to lead to the first safe and effective product to address renarcotization, and will lead to a positive impact on public health.